1. Field of the Invention
This invention relates to compositions of matter, and methods of using said compositions for inhibiting human reductase enzyme(s) that destroy the cell-killing efficacy of anthracycline cancer drugs and that catalyze the formation of dangerous or damaging metabolites during or after cancer treatment. More specifically, embodiments of the invented compositions and methods inhibit human carbonyl reductase, thus inhibiting conversion of anthracycline to metabolites that are less effective cell-killing agents and that also lead to cardiotoxicity during or after treatment of cancer patients. Thus, the invented compositions and methods are believed to lower the amount needed, and the cardiotoxic side-effects, of anthracyclines in cancer treatment.
2. Related Art
Anthracyclines are a family of drugs that are effective anti-neoplastic agents, and are commonly used to treat cancer, including leukemia, soft tissue sarcomas, and breast and lung cancer. Anthracyclines intercalate into DNA and are described as topoisomerase Type II poisons. The anthracycline family comprises adriamycin, daunomycin, daunorubicin, doxorubicin, epirubicin, and idarubicin. See, for example, representations of doxorubicin and daunorubicin in FIG. 1.
While the anthracyclines are known to be potent anti-tumor drugs, their use has been limited due to potentially life-threatening cardiotoxicity associated therewith. This problem may be described as cumulative dose-dependent cardiotoxicity, which can ultimately result in congestive heart failure. There is significant evidence that the toxic effects on the heart alcohol metabolite(s) that can form and accumulate in cardiac cells. These metabolites are known to disrupt several key processes in heart muscle and thus impair heart function. See, for example, Minotti, et al., “Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardioitoxicity,” Pharmacological Reviews, 56: 185-229, 2004.
Enzymes belonging to the aldo-keto reductase and short chain dehydrogenase/reductase protein superfamilies catalyze the formation of the anthracycline metabolites. Of these enzymes, carbonyl reductase (“CR”) has been specifically linked to the development of anthracycline-induced cardiotoxicity. See, for example, Olson, et al., “Protection from Doxorubicin-Induced Cardiac Toxicity in Mice with a Null Allele of Carbonyl Reductase 1,” Cancer Research, 63, 6602-6606, Oct. 15, 2003. Findings that support the hypothesis that CR is a key factor in anthracycline-induced cardiotoxicity include studies wherein heart-specific over-expression of human carbonyl reductase in transgenic mice substantially increased the development of cardiotoxicity after anthracycline treatment. See, for example, Forrest, et al., “Human Carbonyl Reductase Overexpression in the Heart Advances the Development of Doxorubicin-induced Cardiotoxicity in Transgenic Mice,” Cancer Research, 60, 5158-5164, Sep. 15, 2000.
Further, several studies have implicated the reduction of anthracyclines by carbonyl reductase in drug resistance. This is largely because the alcohol metabolites of anthracyclines have been shown to exhibit significantly lowered anticancer properties. Relevant to this are studies performed by Tanaka, et al., (reported in Tanaka, et al., “An Unbiased Cell Morphology-Based Screen for New, Biologically Active Small Molecules,” PLoS Biology, Vol. 3, Iss. 5, 0764-0776, May 2005). Tanaka, et al. report that a potent inhibitor of human carbonyl reductase (3-(7-isopropyl-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol, when coadministered with daunorubicin to A549 adenocarcinoma cells, was found to enhance the cytotoxicity of daunorubicin. It was concluded that inhibition of carbonyl reductase led to enhanced cytotoxicity of daunorubicin.
See, for example, the FIG. 2 representation of carbonyl reductase catalysis (reduction via NADPH+H+ mechanism) of the anthracycline daunorubicin to daunorubicinol. While daunorubicin is an effective anti-cancer agent by means of its effective disruption of DNA replication, daunorubicinol exhibits reduced anti-cancer properties and is a potent cardiotoxin. Therefore, conversion to the alcohol metabolite not only creates a potent cardiotoxin, but also lowers the efficacy of the treatment for a given amount of anthracycline.
Therefore, the inventor believes that there is a need for pharmaceutical interventions that block the action of human carbonyl reductase. The inventor believes that such pharmaceutical interventions will increase the efficacy of anthracycline therapy in cancer/tumor treatment by preventing or lowering conversion of anthracyclines to less potent cell-killing species and by reducing the risk of cardiotoxicity.